This study was conducted to determine if alterations in hippocampal protein kinase C (PKC) gamma is one of the cellular mechanisms by which conventional antiepileptic drugs affect learning and memory. Wistar Rats (21-day-old) were divided into five groups: (1) control (no training and drugs); (2) training group (no drugs (3) phenobarbital (PB) group; (4) carbamazepine (CBZ) group;, and (5) valproate (VPA) group. A hippocampus dependent learning task (spatial changing learning) was used in the latter four groups lasting a total of 10 days. Correct responding rate of training group was significantly higher (P < 0.05) than in the PB, CBZ and VPA group. The PKC gamma staining intensity in hippocampal CA1-2 region of training group was significant greater than that of the control and PB group. There was no difference in staining intensities between the CBZ, VPA group or training group. The amount of PKC gamma located in plasma membrane of hippocampal neurons was significantly higher in the training group (P < 0.05) than the control, PB and VPA groups. No differences were found between the training and CBZ group. Lastly, the amount of PKC gamma in cytosol of hippocampus did not significantly differ between any of the five groups. These results indicate that the three antiepileptic drugs used in this study all disturbed the spatial learning of immature rats. Spatial learning was concomitant with activation of PKC gamma in hippocampal neurons. PB and VPA likely adversely affect learning and memory by interfering with PKC gamma activation, whereas CBZ may act by a different mechanism, possibly in the post-translocation process or by a PKC gamma independent pathway. (C) 2002 Published by Elsevier Science B.V.